1. Field of the Invention
The present invention relates generally to novel ether-esters derived from kojic acid. More particularly, the compounds of the invention are represented by the formula I ##STR2## wherein R and R.sub.1 are different and represent --(CH.sub.2).sub.n -alkoxy of from about 10 to 20 carbon atoms; ##STR3## wherein R.sub.2 is straight or branched chain alkyl of from about 1 to 6 carbon atoms; aralkyl of from about 6 to 15 carbon atoms; benzyloxy; or the group ##STR4## and n is 0 or 1; and the pharmaceutically acceptable non-toxic salts thereof.
The present invention is further directed to pharmaceutical compositions and methods for inhibiting or controlling physiological levels of active proteases, especially elastase, in biological tissues and, thus, the ultimate mitigation or prevention of elastase mediated connective tissue diseases or conditions. The pharmaceutical compositions comprise a pharmaceutically acceptable non-toxic carrier in combination with an active derivative of formula I. The method comprises the administration of a therapeutically, e.g., anti-inflammatory, effective amount of a derivative of formula I.
Proteases or protein splitting enzymes are proteins whose function is to alter or decompose other proteins by splitting them into fragments. They are essential in a variety of physiological activities such as digestion, formation and dissolution of blood clots, the repair or removal of damaged or injured tissues, the removal of tissue debris, the immune reaction to foreign cells and organisms and inflammatory processes, among others.
While the proteases serve important biological functions, they are controlled by a mechanism which prevents them from indiscriminately destroying any protein within their presence. The mechanism includes protease inhibitors which bind with the proteases and prevent their protein fragmentation action. For further information, see "A Family of Protein cutting Proteases", Scientific American, R. M. Stroud, July 1974, pages 74-78.
In general, proper function of the control mechanism is important for the health of the host organism. A protease-inhibitor imbalance can produce an excess of protease and permit the undesirable degradation of structural proteins such as elastin, collagen, and proteoglycan. It can be seen that dysfunction of the control mechanism can lead to connective tissue destruction and disease.
The protease, elastase, is believed to play an important part in the etiology of inflammatory connective tissue disease. It fragments elastin, a functional protein component of connective tissue, as well as other proteins and, hence, can reduce the elastic expansion and contraction of the lungs and the cardiovascular system and can destroy the resiliency and elasticity of joints. As a result, the function, elasticity and resiliency of organs containing elastin can be adversely affected and the organs will eventually undergo trophic changes, including the loss of elastic tissue, as occurs in such diseases as rheumatoid arthritis, pulmonary emphysema, chronic obstructive pulmonary disease, atherosclerosis, pseudoxanthoma elasticum, X-linked cutis laxa, Menke's kinky-hair syndrome, and Ehlers-Danlos syndrome, Type V.
Further indications of the relation between elastase and connective tissue disease have been shown by animal model studies and by joint tissue studies. For example, papain and porcine pancreatic elastase are elastase-like proteases which have been used experimentally to produce emphysema-like disease in animal models. Human leukocyte elastase, extracted from human polymorphonuclear leukocytes, has also been instilled intratracheally into animals to produce a disease resembling human emphysema. The physiological and morphological results of elastase induced emphysema in such animal models and the corresponding animal symptoms and biochemistry have been compared to the disease in man, and these tests have shown an association between elastase and emphysema; see Sandberg, et al., The New England Journal of Medicine, 304, 566, (1981).
Rheumatoid arthritis is another example of a disease which has been linked to inhibitor-protease imbalance. In the course of this disease, polymorphonuclear leukocytes are released and enter acute inflammatory exudates to phagocytize immune reactants and cellular material thereby releasing elastase. When the elastase release overwhelms the inhibitors present in the local tissue, phagocytosis proceeds not only upon material which should be removed but upon the healthy tissue and hence causes greatly enhanced tissue damage. The major portion of this proteolytic activity has been attributed to elastase. See, for example, Janoff, Biochem. J., 114, 157 (1969) and Wong, Travis, Biochem. Biophys. Res. Comm., 96, 1449 (1980).
Research into inflammatory diseases involving proteolytic enzymes has sought to isolate and characterize endogenous protease inhibitors present in biological tissues. Human serum .alpha..sub.1 -antitrypsin and .alpha..sub.2 -macroglobin are two known endogenous inhibitors. Synthetic inhibitors have also been studied; see U.S. Pat. No. 4,195,023. In general, however, little work has been done to produce a synthetic inhibitor which is highly active, produces desirable results in models of elastase related disease and is relatively free of harmful side effects.
2. State of the Art
U.S. Pat. No. 3,968,236 discloses 2-aminomethyl-5-hydroxy-4H-pyran-4-one and derivatives having skeletal muscle relaxant properties. No ether-ester(s) (or ester precursors) are disclosed and the compounds are not indicated to have any anti- inflammatory/elastase inhibitory properties.
2-Iodomethyl-5-hydroxy-6-bromo-4-pyrone, 2-iodomethyl-5-hydroxy-4-pyrone and related 2-,5-,6-substituted kojic acid derivatives which are not ether-ester derivatives of formula I are disclosed in Chem. Abstracts, Vol. 78, 119672w as having antibacterial activity.
U.S. Pat. No. 4,278,656 discloses aliphatic mono- and di-esters, particularly diesters, of kojic acid as useful in skin whitener cosmetic compositions. None of the compounds disclosed comprise derivatives wherein one of the substituents is an ether.
5-Acetoxy-2-(methoxymethyl)-4H-pyran-4-one is disclosed as one of three reaction products formed by the acetylation of 1,3-di-O-acetyl-4,6,di-O-methyl-.alpha.-D-arabino-hexopyranosulose in Chem. Abstracts. Vol. 78, 124816a. No long-chain aliphatic ether-esters or elastase inhibitory properties thereof are disclosed.